CN116947592A - Preparation method of 2, 7-dichlorofluorene derivative - Google Patents
Preparation method of 2, 7-dichlorofluorene derivative Download PDFInfo
- Publication number
- CN116947592A CN116947592A CN202210387684.XA CN202210387684A CN116947592A CN 116947592 A CN116947592 A CN 116947592A CN 202210387684 A CN202210387684 A CN 202210387684A CN 116947592 A CN116947592 A CN 116947592A
- Authority
- CN
- China
- Prior art keywords
- dichlorofluorene
- acid
- fluorene
- catalyst
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- SDPURBHAHVFTGX-UHFFFAOYSA-N 2,7-dichloro-9h-fluorene Chemical class ClC1=CC=C2C3=CC=C(Cl)C=C3CC2=C1 SDPURBHAHVFTGX-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims abstract description 99
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229950009390 symclosene Drugs 0.000 claims abstract description 29
- 239000003960 organic solvent Substances 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 14
- -1 fluorene compound Chemical class 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 3
- 230000008569 process Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 230000035484 reaction time Effects 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 11
- 239000012320 chlorinating reagent Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- 239000002244 precipitate Substances 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 7
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 claims description 4
- 150000007517 lewis acids Chemical group 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- JGDITNMASUZKPW-UHFFFAOYSA-K aluminium trichloride hexahydrate Chemical compound O.O.O.O.O.O.Cl[Al](Cl)Cl JGDITNMASUZKPW-UHFFFAOYSA-K 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- DLHTWZBWWPZUSD-UHFFFAOYSA-N aluminum nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Al+3] DLHTWZBWWPZUSD-UHFFFAOYSA-N 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 25
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
- 239000011968 lewis acid catalyst Substances 0.000 description 18
- 238000003760 magnetic stirring Methods 0.000 description 17
- 239000003377 acid catalyst Substances 0.000 description 16
- 239000002801 charged material Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 14
- 239000000463 material Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- ZBQLAOVNDBNMFI-UHFFFAOYSA-N 9-benzyl-9h-fluorene Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1CC1=CC=CC=C1 ZBQLAOVNDBNMFI-UHFFFAOYSA-N 0.000 description 3
- QBBCCEYJCKGWIK-UHFFFAOYSA-N 9-ethyl-9h-fluorene Chemical compound C1=CC=C2C(CC)C3=CC=CC=C3C2=C1 QBBCCEYJCKGWIK-UHFFFAOYSA-N 0.000 description 3
- ZVEJRZRAUYJYCO-UHFFFAOYSA-N 9-methyl-9h-fluorene Chemical compound C1=CC=C2C(C)C3=CC=CC=C3C2=C1 ZVEJRZRAUYJYCO-UHFFFAOYSA-N 0.000 description 3
- 239000003430 antimalarial agent Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 150000002220 fluorenes Chemical class 0.000 description 3
- DYLGFOYVTXJFJP-MYYYXRDXSA-N lumefantrine Chemical compound C12=CC(Cl)=CC=C2C=2C(C(O)CN(CCCC)CCCC)=CC(Cl)=CC=2\C1=C/C1=CC=C(Cl)C=C1 DYLGFOYVTXJFJP-MYYYXRDXSA-N 0.000 description 3
- 229960004985 lumefantrine Drugs 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- YJUGSXRBZQIGIQ-UHFFFAOYSA-N 2,7-dichloro-9-ethyl-9h-fluorene Chemical compound C1=C(Cl)C=C2C(CC)C3=CC(Cl)=CC=C3C2=C1 YJUGSXRBZQIGIQ-UHFFFAOYSA-N 0.000 description 2
- NRISTVRQRDZEOY-UHFFFAOYSA-N 2,7-dichloro-9-methyl-9h-fluorene Chemical compound C1=C(Cl)C=C2C(C)C3=CC(Cl)=CC=C3C2=C1 NRISTVRQRDZEOY-UHFFFAOYSA-N 0.000 description 2
- ZKLFRQSZDUSMQE-UHFFFAOYSA-N 5,5-dichloroimidazolidine-2,4-dione Chemical compound ClC1(Cl)NC(=O)NC1=O ZKLFRQSZDUSMQE-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 230000000078 anti-malarial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007336 electrophilic substitution reaction Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 201000004792 malaria Diseases 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229960000981 artemether Drugs 0.000 description 1
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 1
- 229960004191 artemisinin Drugs 0.000 description 1
- 229930101531 artemisinin Natural products 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- JSYGRUBHOCKMGQ-UHFFFAOYSA-N dichloramine Chemical compound ClNCl JSYGRUBHOCKMGQ-UHFFFAOYSA-N 0.000 description 1
- SXYIRMFQILZOAM-HVNFFKDJSA-N dihydroartemisinin methyl ether Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-HVNFFKDJSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- ARGDYOIRHYLIMT-UHFFFAOYSA-N n,n-dichloro-4-methylbenzenesulfonamide Chemical compound CC1=CC=C(S(=O)(=O)N(Cl)Cl)C=C1 ARGDYOIRHYLIMT-UHFFFAOYSA-N 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/12—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the ring of aromatic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 2, 7-dichloro fluorene derivative, which takes fluorene compound shown in formula (II) as raw material, reacts with chloro-agent trichloroisocyanuric acid in organic solvent under the action of catalyst at a certain temperature, and the obtained reaction liquid is separated and purified to obtain the 2, 7-dichloro fluorene derivative shown in formula (I),wherein the substituent R is substituted or unsubstituted, and when substituted, the substituent R is CH 3 ‑、C 2 H 5 ‑、Bn‑、C 6 H 5 ‑、CH 3 O‑、C 2 H 5 O-or C 6 H 5 O-. The preparation method of the invention has the advantages of cheap and easily available raw materials, environmental protection, simple process, simple and convenient operation, high purity, good yield and the like, accords with the concept of green pharmacy, and is suitable for industrial production。
Description
Technical Field
The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and particularly relates to a preparation method of a 2, 7-dichlorofluorene derivative.
Background
Fluorene derivatives are widely applied to various fields of material science, organic chemistry, pharmaceutical chemistry and the like, wherein 2, 7-dichlorofluorene is taken as an important intermediate of antimalarial medicine benflumetol in the industry. There are two main classes of drugs for the treatment of malaria, but the drugs quinine, chloroquine and artemisinin, which have been developed to control clinical attacks, have developed resistance. In order to solve the problem of drug resistance, the world health organization asserts the combined drug, and the artemether-lumefantrine compound preparation is the first choice drug for treating malaria at present. The compound medicine is currently accepted into the basic catalogue of antimalarial medicines of the world health organization, and the compound proportion is artemether: lumefantrine=1:6, whereas 2, 7-dichlorofluorene is a traditional Chinese medicine intermediate of antimalarial drug lumefantrine.
The current synthesis method of 2, 7-dichlorofluorene mainly comprises the following steps:
1) In 1992, the institute of epidemiology in the national academy of sciences of military medicine tried a synthesis method using N-chlorosuccinimide (NCS) as a chlorinating agent (Wang Jian, zhong Jingxing, journal of the national academy of military medicine, 1992, (4): 302-303.) this method avoided reflux by heating, saved resources, but the reaction time was too long, and the raw materials were expensive and the cost was too high.
2) In 1992, the institute of epidemiology in microbiology, the academy of military medical science, also tried a synthesis method using dichloramine T as a chlorinating agent in concentrated H 2 SO 4 Under catalysis, 2, 7-dichlorofluorene is obtained through electrophilic substitution reaction, the yield is only 33%, the yield of the method is low, the method has one-step auxiliary reaction, the period is too long, and most importantly, the dichloroamine T pollutes the environment, and the three wastes are not well treated (Wang Jian, zhong Jingxing, proc. Natl. Acad. Sci. Of military medical science, 1992, (4): 302-303.).
3) Chinese patent CN103193588A discloses a process for preparing a catalyst by Cl 2 As a chlorinating agent, the method for producing 2, 7-dichlorofluorene on a large scale is a main method, and the reaction is an electrophilic substitution chlorination reaction of which the aromatic ring is typical, and the chlorine gas as the chlorinating agent has the practical problems of inconvenient gas dosage, more byproducts, large residual halogen amount, high requirements on environment-friendly equipment, environment-friendly process control difficulty, troublesome three-waste treatment and the like.
4) Chinese patent CN102786399A discloses that 2, 7-dichlorofluorene is obtained by taking dichlorohydantoin as a chlorinating agent and reacting under an acidic condition, the yield is 54%, the method adopts a novel chlorinating agent dichlorohydantoin, the selectivity is good, the yield is considerable, and the defects of poor selectivity and low chlorination efficiency of the traditional chlorinating agent of chlorine are overcome, but one-step auxiliary reaction is needed, and the reaction time is too long.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a method for preparing 2, 7-dichlorofluorene derivatives by taking fluorene compounds as starting materials, which has the characteristics of simple process, simple and convenient operation, low cost, environmental protection, good yield and the like.
In order to achieve the above purpose, the following technical scheme is provided:
a process for preparing 2, 7-dichloro fluorene derivative includes such steps as reacting fluorene compound as shown in formula (II) with trichloroisocyanuric acid as chlorinating agent in organic solvent at a certain temp under the action of catalyst, separating and purifying the resultant reaction liquid to obtain 2, 7-dichloro fluorene derivative as shown in formula (I),
wherein the substituent R is substituted or unsubstituted, and when substituted, the substituent R is CH 3 -、C 2 H 5 -、Bn-、C 6 H 5 -、CH 3 O-、C 2 H 5 O-or C 6 H 5 O-。
Further, the catalyst is Lewis acid or protonic acid, wherein the protonic acid is concentrated hydrochloric acid, concentrated sulfuric acid or H 3 PO 4 Or sulfonic acid, the Lewis acid is anhydrous aluminum chloride, stannic chloride, hexahydrate aluminum chloride or nonahydrate ferric nitrate, and is preferably concentrated hydrochloric acid, concentrated sulfuric acid, anhydrous aluminum chloride or stannic chloride.
Further, the organic solvent is 1, 2-dichloroethane, toluene, isopropyl ether, ethyl acetate, dimethyl sulfoxide, acetonitrile, N-dimethylformamide, N-dimethylacetamide, ethanol or dichloromethane.
Further, the fluorene compound, trichloroisocyanuric acid and catalyst shown in the formula (II) are used in the following amount ratio: trichloroisocyanuric acid: the catalyst is 1.0:0.7-2.5:0.01-0.5.
Further, the reaction time is 3-6 hours.
Further, the reaction process is controlled to be at a temperature of-10 to 60 ℃.
Further, the mass ratio of the volume usage of the organic solvent to the fluorene compound shown in the formula (II) is 3-6:1, the volume unit is mL, and the mass unit is g.
Further, the specific separation and purification process is as follows: filtering after the reaction is finished, washing the precipitate with ethanol, dissolving the precipitate with ethyl acetate, filtering out insoluble matters, spin-drying to recover ethyl acetate, and drying to obtain the 2, 7-dichlorofluorene derivative shown in the formula (I).
The invention has the beneficial effects that:
1) The preparation method is simple and convenient to operate, the raw material trichloroisocyanuric acid is cheap and easy to obtain, the reaction can be carried out under mild conditions, the yield is high, and the method is suitable for industrial production;
2) The preparation method of the invention is environment-friendly and avoids using Cl 2 When the catalyst is used as a chlorinating agent, the catalyst can be carried out only by a catalytic amount of an acid system.
Detailed Description
The technical scheme of the present invention is described by the following specific examples, but the scope of the present invention is not limited thereto.
Example 1 Synthesis of 2, 7-dichlorofluorene
In a 250mL three-necked round bottom flask equipped with a magnetic stirrer and thermometer were charged fluorene (20 g, 120.32 mmol) and trichloroisocyanuric acid (69.91 g, 300.80 mmol), 0 as starting materials o Adding acetonitrile (80 mL) serving as a solvent, mechanically stirring and cooling to 0 ℃, slowly dropwise adding a concentrated hydrochloric acid solution (0.61 g,6.02 mmol) serving as a catalyst, stirring at 0 ℃ for reaction for 4 hours after the dropwise adding is finished, tracking the reaction progress by HPLC, filtering after the reaction is finished, washing a precipitate by 30mL of ethanol, dissolving by 100mL of ethyl acetate, filtering off insoluble substances, spin-drying and recovering the ethyl acetate, drying and weighing to obtain 24.73g of white or light yellow crystalline solid, wherein the yield is 87.42%, the HPLC purity is 98.64%, and the melting point is 126-128 ℃.
1 H NMR (600 MHz, DMSO-d 6 ) ：δ 7.91 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 1.9 Hz, 2H), 7.43 (dd, J = 8.2, 2.0 Hz, 2H), 3.94 (s, 2H)。
Example 2
In a 250mL three-necked round bottom flask equipped with magnetic stirring and thermometer, fluorene was added in the following ratio by amount of the charged materials: trichloroisocyanuric acid: the Lewis acid catalyst was 1.0:2.0:0.3 feeding, wherein the dosage of fluorene is 20g, the Lewis acid catalyst is stannic chloride, the organic solvent is N, N-dimethylformamide, and the ratio of the volume dosage of N, N-dimethylformamide to the mass dosage of fluorene is 5ml:1g, a reaction temperature of 0 ℃ and a reaction time of 5 hours, and 25.31g of 2, 7-dichlorofluorene is obtained by the other operations in example 1, the product yield is 89.47%, the HPLC purity is 99.13%, and the melting point is 126-128 ℃.
Example 3
In a 250mL three-necked round bottom flask equipped with magnetic stirring and thermometer, fluorene was added in the following ratio by amount of the charged materials: trichloroisocyanuric acid: the protonic acid catalyst was 1.0:2.4:0.15 of fluorene, wherein the dosage of the fluorene is 20g, the proton acid catalyst is concentrated hydrochloric acid, the organic solvent is N, N-dimethylformamide, and the ratio of the volume dosage of the N, N-dimethylformamide to the mass dosage of the fluorene is 4ml:1g, a reaction temperature of 25 ℃ and a reaction time of 4.5 hours, and 24.57g of 2, 7-dichlorofluorene is obtained by the other operations of example 1, the product yield is 86.85%, the HPLC purity is 99.51%, and the melting point is 126-128 ℃.
Example 4
In a 250mL three-necked round bottom flask equipped with magnetic stirring and thermometer, fluorene was added in the following ratio by amount of the charged materials: trichloroisocyanuric acid: the protonic acid catalyst was 1.0:0.8:0.4 of material, wherein the dosage of fluorene is 20g, the proton acid catalyst is concentrated sulfuric acid, the organic solvent is N, N-dimethylformamide, and the ratio of the volume dosage of N, N-dimethylformamide to the mass dosage of fluorene is 4ml:1g of 2, 7-dichlorofluorene is obtained by the same operation as in example 1, wherein the reaction temperature is 0 ℃ and the reaction time is 4 hours, the yield of the 2, 7-dichlorofluorene is 85.75%, the HPLC purity is 99.53%, and the melting point is 126-128 ℃.
Example 5
In a 250mL three-necked round bottom flask equipped with magnetic stirring and thermometer, fluorene was added in the following ratio by amount of the charged materials: trichloroisocyanuric acid: the Lewis acid catalyst was 1.0:2.0:0.10 of material, wherein the dosage of fluorene is 20g, the Lewis acid catalyst is anhydrous aluminum trichloride, the organic solvent is acetonitrile, and the ratio of the volume dosage of acetonitrile to the mass dosage of fluorene is 4ml:1g of 2, 7-dichlorofluorene was obtained in 23.95g of the same manner as in example 1 except that the reaction temperature was 25℃and the reaction time was 5 hours, the yield of the product was 84.66%, the HPLC purity was 98.55% and the melting point was 126 to 128 ℃.
Example 6
In a 250mL three-necked round bottom flask equipped with magnetic stirring and thermometer, fluorene was added in the following ratio by amount of the charged materials: trichloroisocyanuric acid: the Lewis acid catalyst was 1.0:1.0:0.10 charge, fluorene amount is 20g, wherein Lewis acid catalyst is hexahydrate aluminum trichloride, organic solvent is 1, 2-dichloroethane, volume amount of 1, 2-dichloroethane and mass amount ratio of fluorene is 6 ml:1g, a reaction temperature of 0 ℃ and a reaction time of 5 hours, and 19.66g of 2, 7-dichlorofluorene is obtained by the other operations in example 1, the product yield is 69.49%, the HPLC purity is 92.04%, and the melting point is 126-128 ℃.
Example 7
In a 250mL three-necked round bottom flask equipped with magnetic stirring and thermometer, fluorene was added in the following ratio by amount of the charged materials: trichloroisocyanuric acid: the protonic acid catalyst was 1.0:0.75:0.25 of material, wherein the dosage of fluorene is 20g, the proton acid catalyst is concentrated hydrochloric acid, the organic solvent is acetonitrile, and the ratio of the volume dosage of acetonitrile to the mass dosage of fluorene is 4ml:1g of 2, 7-dichlorofluorene 22.52g was obtained in the same manner as in example 1 except that the reaction temperature was 60℃and the reaction time was 4.5 hours, the product yield was 79.60%, the HPLC purity was 98.65% and the melting point was 126 to 128 ℃.
Example 8
In a 250mL three-necked round bottom flask equipped with magnetic stirring and thermometer, fluorene was added in the following ratio by amount of the charged materials: trichloroisocyanuric acid: the protonic acid catalyst was 1.0:1.15:0.15 of material, wherein the dosage of fluorene is 20g, the proton acid catalyst is concentrated hydrochloric acid, the organic solvent is toluene, and the ratio of the volume dosage of toluene to the mass dosage of fluorene is 6 ml:1g of 2, 7-dichlorofluorene 21.13g is obtained by the same operation as in example 1, wherein the reaction temperature is 60 ℃ and the reaction time is 4 hours, the product yield is 74.69%, the HPLC purity is 92.42%, and the melting point is 126-128 ℃.
Example 9
In a 250mL three-necked round bottom flask equipped with magnetic stirring and a thermometer, fluorene was added according to the mass ratio of the materials fed: trichloroisocyanuric acid: the protonic acid catalyst was 1.0:2.0:0.2 of fluorene, wherein the dosage of fluorene is 20g, the proton acid catalyst is sulfonic acid, the organic solvent is N, N-dimethylformamide, and the ratio of the volume dosage of N, N-dimethylformamide to the mass dosage of fluorene is 6 ml:1g, a reaction temperature of 25 ℃ and a reaction time of 4 hours, and 20.41g of 2, 7-dichlorofluorene is obtained by the other operations in example 1, the product yield is 72.15%, the HPLC purity is 97.65%, and the melting point is 126-128 ℃.
Example 10
In a 250mL three-necked round bottom flask equipped with magnetic stirring and thermometer, fluorene was added in the following ratio by amount of the charged materials: trichloroisocyanuric acid: the Lewis acid catalyst was 1.0:1.75:0.3 of feeding, wherein the dosage of fluorene is 20g, the Lewis acid catalyst is stannic chloride, the organic solvent is isopropyl ether, and the ratio of the volume dosage of the isopropyl ether to the mass dosage of fluorene is 6 ml:1g, a reaction temperature of 45 ℃ and a reaction time of 6 hours, and the other operations are the same as in example 1, so as to obtain 16.02g of 2, 7-dichlorofluorene, wherein the product yield is 56.63%, the HPLC purity is 94.58%, and the melting point is 126-128 ℃.
Example 11
In a 250mL three-necked round bottom flask equipped with magnetic stirring and thermometer, fluorene was added in the following ratio by amount of the charged materials: trichloroisocyanuric acid: the protonic acid catalyst was 1.0:1.0:0.05 charge, fluorene amount is 20g, wherein the protonic acid catalyst is H 3 PO 4 The organic solvent is N, N-dimethylacetamide, and the ratio of the volume usage amount of the N, N-dimethylacetamide to the mass usage amount of fluorene is 3ml:1g of 2, 7-dichlorofluorene is obtained by the same operation as in example 1, wherein the reaction temperature is-5 ℃ and the reaction time is 3 hours, the yield of the 2, 7-dichlorofluorene is 65.45 g, the HPLC purity is 99.51%, and the melting point is 126-128 ℃.
Example 12
In a 250mL three-necked round bottom flask equipped with magnetic stirring and thermometer, fluorene was added in the following ratio by amount of the charged materials: trichloroisocyanuric acid: the protonic acid catalyst was 1.0:1.25:0.25 of material, wherein the dosage of fluorene is 20g, the proton acid catalyst is concentrated sulfuric acid, the organic solvent is absolute ethyl alcohol, and the ratio of the volume dosage of the absolute ethyl alcohol to the mass dosage of fluorene is 4ml:1g of 2, 7-dichlorofluorene is obtained by the same operation as in example 1 except that the reaction temperature is 0 ℃ and the reaction time is 5.5 hours, the yield of the product is 64.79%, the HPLC purity is 94.88%, and the melting point is 126-128 ℃.
Example 13
In a 250mL three-necked round bottom flask equipped with magnetic stirring and thermometer, fluorene was added in the following ratio by amount of the charged materials: trichloroisocyanuric acid: the Lewis acid catalyst was 1.0:1.5:0.02 of feeding, wherein the dosage of fluorene is 20g, the Lewis acid catalyst is anhydrous aluminum trichloride, the organic solvent is ethyl acetate, and the ratio of the volume dosage of the ethyl acetate to the mass dosage of fluorene is 3ml:1g, a reaction temperature of 45 ℃ and a reaction time of 5 hours, and 18.19g of 2, 7-dichlorofluorene is obtained by the other operations in example 1, the product yield is 64.29%, the HPLC purity is 93.62%, and the melting point is 126-128 ℃.
Example 14
In a 250mL three-necked round bottom flask equipped with magnetic stirring and thermometer, fluorene was added in the following ratio by amount of the charged materials: trichloroisocyanuric acid: the Lewis acid catalyst was 1.0:1.25:0.05 of material, wherein the dosage of fluorene is 20g, the Lewis acid catalyst is anhydrous aluminum trichloride, the organic solvent is dichloromethane, and the ratio of the volume dosage of the dichloromethane to the mass dosage of the fluorene is 3ml:1g, a reaction temperature of 0 ℃ and a reaction time of 5 hours, and 17.78g of 2, 7-dichlorofluorene is obtained by other operations in example 1, the product yield is 62.85%, the HPLC purity is 99.35%, and the melting point is 126-128 ℃.
Example 15
In a 250mL three-necked round bottom flask equipped with magnetic stirring and thermometer, fluorene was added in the following ratio by amount of the charged materials: trichloroisocyanuric acid: the protonic acid catalyst was 1.0:1.2:0.2 of material, wherein the dosage of fluorene is 20g, the proton acid catalyst is concentrated sulfuric acid, the organic solvent is dimethyl sulfoxide, and the ratio of the volume dosage of dimethyl sulfoxide to the mass dosage of fluorene is 5ml:1g of 2, 7-dichlorofluorene is obtained by the same operation as in example 1, wherein the reaction temperature is 25 ℃ and the reaction time is 6 hours, the yield of the 2, 7-dichlorofluorene is 54.35 g, the HPLC purity is 92.15%, and the melting point is 126-128 ℃.
Example 16
In a 250mL three-necked round bottom flask equipped with a magnetic stirrer and a thermometer, 9-methylfluorene (20 g, 110.96 mmol) and trichloroisocyanuric acid (30.94 g, 133.15 mmol) as raw materials were added, acetonitrile (80 mL) as a solvent was added at 25℃and a concentrated hydrochloric acid solution (3.37 g,33.29 mmol) as a catalyst was slowly added dropwise at 25℃and stirred at 25℃for 5 hours after the completion of the dropwise addition, the reaction was followed by HPLC, filtration after the completion of the reaction, washing of the precipitate with 30mL of ethanol, dissolution with 100mL of ethyl acetate, filtration of insoluble matters, recovery of ethyl acetate by spin drying, drying and weighing to obtain 19.91g of 2, 7-dichloro-9-methyl-9H-fluorene having a yield of 72.03%, an HPLC purity of 98.15% and a melting point of 128 ℃.
Example 17
In a 250mL three-necked round bottom flask equipped with magnetic stirring and thermometer, 9-methylfluorene was added in the following ratio by amount of the charged materials: trichloroisocyanuric acid: the Lewis acid catalyst was 1.0:1.5:0.05 of material, wherein the dosage of 9-methylfluorene is 20g, the Lewis acid catalyst is aluminum trichloride, the organic solvent is N, N-dimethylacetamide, and the ratio of the volume dosage of the N, N-dimethylacetamide to the mass dosage of fluorene compounds is 5ml:1g, reaction temperature 0 ℃, reaction time 3 hours, and other operations are the same as in example 16, thus obtaining 17.23g of 2, 7-dichloro-9-methyl-9H-fluorene, product yield 62.34%, HPLC purity 92.94%, melting point 128 ℃.
Example 18
In a 250mL three-neck round bottom flask equipped with a magnetic stirrer and a thermometer, raw materials of 9-ethyl fluorene (20 g, 102.95 mmol) and trichloroisocyanuric acid (47.85 g, 205.89 mmol) are added, solvent N, N-dimethylformamide (80 mL) is added at 0 ℃, the temperature is reduced to 0 ℃, concentrated sulfuric acid solution (1.55 g,15.44 mmol) serving as a catalyst is slowly added dropwise at 0 ℃, the temperature is raised to 45 ℃ after the completion of the dropwise addition, the reaction is stirred at 45 ℃ for 3 hours, the reaction progress is tracked by HPLC, the reaction is filtered after the completion, the precipitate is washed with 30mL ethanol and then is dissolved with 100mL ethyl acetate, insoluble matters are filtered off, ethyl acetate is recovered by spin drying, the dried and weighed, and the 2, 7-dichloro-9-ethyl-9H-fluorene 18.52g is obtained, the yield is 68.36%, and the HPLC purity is 98.42%.
Example 19
In a 250mL three-necked round bottom flask equipped with magnetic stirring and thermometer, 9-ethylfluorene was added in the following ratio by amount of the charged materials: trichloroisocyanuric acid: the Lewis acid catalyst was 1.0:1.1:0.4 of material, wherein the dosage of 9-ethyl fluorene is 20g, the Lewis acid catalyst is anhydrous stannic chloride, the organic solvent is ethyl acetate, and the mass ratio of the volume dosage of the ethyl acetate to the mass dosage of fluorene compound is 6 ml:1g, reaction temperature 25 ℃, reaction time 4 hours, and other operations are the same as in example 18, thus obtaining 14.82g of 2, 7-dichloro-9-ethyl-9H-fluorene, product yield 54.71% and HPLC purity 91.75%.
Example 20
In a 250mL three-neck round bottom flask equipped with a magnetic stirrer and a thermometer, raw materials of 9-benzyl fluorene (20 g, 78.02 mmol) and trichloroisocyanuric acid (19.94 g, 85.82 mmol) are added, solvent 1, 2-dichloroethane (80 mL) is added at 0 ℃, the temperature is reduced to 0 ℃, concentrated sulfuric acid solution (2.34 g,23.41 mmol) serving as a catalyst is slowly added dropwise at 0 ℃, the dropwise addition is completed, the reaction is stirred at 0 ℃ for 5 hours, HPLC tracks the reaction progress, filtration is carried out after the reaction is completed, the precipitate is washed with 30mL of ethanol and then is dissolved with 100mL of ethyl acetate, insoluble matters are filtered off, ethyl acetate is recovered by spin drying, drying and weighing are carried out, and 9-benzyl-2, 7-dichloro-9H-fluorene 15.74g is obtained, the yield is 62.04%, the HPLC purity is 96.58%, and the melting point is 110-111 ℃.
Example 21
In a 250mL three-necked round bottom flask equipped with magnetic stirring and thermometer, 9-benzylfluorene was added in the following ratio by amount of the charged materials: trichloroisocyanuric acid: the Lewis acid catalyst was 1.0:2.0:0.25 of material, wherein the dosage of 9-benzyl fluorene is 20g, the Lewis acid catalyst is anhydrous aluminum trichloride, the organic solvent is N, N-dimethylformamide, and the ratio of the volume dosage of N, N-dimethylformamide to the mass dosage of fluorene compound is 3ml:1g, reaction temperature 25 ℃, reaction time 4 hours, and other operations as in example 20, 13.91g of 9-benzyl-2, 7-dichloro-9H-fluorene, product yield 54.83%, HPLC purity 94.59% and melting point 110-111 ℃.
Finally, it should be noted that the above-mentioned embodiments are only for illustrating the technical solution of the present invention and not for limiting the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made to the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention, and it should be covered by the scope of the claims of the present invention.
Claims (8)
1. A process for preparing 2, 7-dichlorofluorene derivative features that fluorene compound as shown in formula (II) is used as raw material, and under the action of catalyst and at a certain temp., the resultant reaction liquid is reacted with trichloroisocyanuric acid as chlorinating agent to obtain 2, 7-dichlorofluorene derivative as shown in formula (I),
wherein the substituent R is substituted or unsubstituted, and when substituted, the substituent R is CH 3 -、C 2 H 5 -、Bn-、C 6 H 5 -、CH 3 O-、C 2 H 5 O-or C 6 H 5 O-。
2. The process for preparing 2, 7-dichlorofluorene derivatives according to claim 1, wherein the catalyst is Lewis acid or protonic acid, wherein the protonic acid is concentrated hydrochloric acid, concentrated sulfuric acid, H 3 PO 4 Or sulfonic acid, the Lewis acid is anhydrous aluminum chloride, stannic chloride, hexahydrate aluminum chloride or nonahydrate ferric nitrate, and is preferably concentrated hydrochloric acid, concentrated sulfuric acid, anhydrous aluminum chloride or stannic chloride.
3. A process for the preparation of a 2, 7-dichlorofluorene derivative according to claim 1, characterized in that the organic solvent is 1, 2-dichloroethane, toluene, isopropyl ether, ethyl acetate, dimethyl sulfoxide, acetonitrile, N-dimethylformamide, N-dimethylacetamide, ethanol or dichloromethane.
4. The method for preparing a 2, 7-dichlorofluorene derivative according to claim 1, wherein the fluorene compound represented by formula (ii), trichloroisocyanuric acid and catalyst are used in the amount ratio of mass: trichloroisocyanuric acid: the catalyst is 1.0:0.7-2.5:0.01-0.5.
5. The method for preparing 2, 7-dichlorofluorene derivatives according to claim 1, wherein the reaction time is 3-6 hours.
6. The method for preparing a 2, 7-dichlorofluorene derivative according to any one of claims 1 to 5, wherein the reaction process is controlled at-10 to 60 ℃.
7. The method for preparing a 2, 7-dichlorofluorene derivative according to claim 1 or 3, wherein the ratio of the volume amount of the organic solvent to the mass amount of the fluorene compound represented by formula (ii) is 3 to 6:1, volume unit is mL, mass unit is g.
8. The preparation method of the 2, 7-dichlorofluorene derivative according to claim 1, which is characterized by comprising the following specific separation and purification processes: filtering after the reaction is finished, washing the precipitate with ethanol, dissolving the precipitate with ethyl acetate, filtering out insoluble matters, spin-drying to recover ethyl acetate, and drying to obtain the 2, 7-dichlorofluorene derivative shown in the formula (I).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210387684.XA CN116947592A (en) | 2022-04-14 | 2022-04-14 | Preparation method of 2, 7-dichlorofluorene derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210387684.XA CN116947592A (en) | 2022-04-14 | 2022-04-14 | Preparation method of 2, 7-dichlorofluorene derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116947592A true CN116947592A (en) | 2023-10-27 |
Family
ID=88447849
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210387684.XA Pending CN116947592A (en) | 2022-04-14 | 2022-04-14 | Preparation method of 2, 7-dichlorofluorene derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116947592A (en) |
-
2022
- 2022-04-14 CN CN202210387684.XA patent/CN116947592A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112679420B (en) | Preparation method of 2,5-dibromopyridine | |
| CN113234077B (en) | Synthesis method of 2-amino-6-chloropurine | |
| CN113121430B (en) | Preparation method of 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone | |
| CN101717359B (en) | Method for synthesizing indapamide | |
| CN110183445A (en) | The synthetic method of Moxifloxacin and its derivative | |
| US20050059692A1 (en) | Process for the preparation of 17beta-N-[2,5-bis(trifluoromethyl)phenyl] carbamoyl-4-aza-5-alpha-androst-1-en-3-one | |
| CN113416150A (en) | Novel synthesis method of lobaplatin intermediate | |
| CN116947592A (en) | Preparation method of 2, 7-dichlorofluorene derivative | |
| CN109761914B (en) | Method for preparing 5-trifluoromethyl uracil | |
| CN113024472B (en) | Preparation method of lung cancer targeting drug dacatinib | |
| CN110256451B (en) | Synthetic method of benzofuro [2,3-b ] quinoline derivative | |
| CN111574520B (en) | Riagliptin intermediate compound V | |
| CN113429379A (en) | LH-1801 intermediate and preparation method and application thereof | |
| CN108658999B (en) | Synthesis method of 2-phenyl heterocyclic [2,3-d ] pyrimidine-4 (3H) -ketone compound | |
| CN111484455A (en) | Synthetic method of 2-chloro-5-fluoro-6-methylpyrimidine | |
| CN116874392B (en) | Preparation method of non-steroidal selective salt corticoid receptor antagonist intermediate 4-aldehyde-3-methoxybenzonitrile | |
| CN113387897B (en) | Method for synthesizing clozapine by photocatalysis | |
| CN110563721A (en) | Preparation method of azasetron hydrochloride | |
| CN113429333B (en) | Synthesis method of gatifloxacin intermediate | |
| CN112358447B (en) | Synthesis method of 7-fluoroisoquinoline-1-carboxylic acid | |
| CN115894435A (en) | Synthesis method of 1- (benzo [ b ] thiophene-4-yl) piperazine hydrochloride | |
| CN108191778B (en) | Method for preparing 2, 3-dichloro quinoxaline derivative by one-pot boiling | |
| CN113582933A (en) | Preparation method of medical intermediate 4-chloro-5-cyanopyrimidine | |
| CN112778220A (en) | Preparation method of benzodiazepine compound D and intermediate thereof | |
| KR100448641B1 (en) | Method for producing phenyl propionic acid derivatives from 2-phenylpropionic acid by simple processing steps with high yield |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |